Based on our murine data, we developed a phase 1 and 2 protocol employing alemtuzumab, 400cGy total body irradiation (TBI) and escalating doses of post-transplant cyclophosphamide (PT-Cy) ranging from 0mg/kg in cohort 1 and 50mg/kg in cohort 2 to 100mg/kg in cohort 3. A total of 21 patients with sickle cell disease and 2 patients with beta thalassemia were transplanted and had complications including cirrhosis, pulmonary hypertension, heart failure, and end-stage renal disease. The engraftment rate improved from 1/3 (33%) in the first cohort, to 5/8 (63%) in the second cohort to 10/12 (83%) in the third cohort. Percentage of donor myeloid and CD3 chimerism also improved with subsequent cohorts. Overall survival is 78.3%; 3 died after return of their sickle cell disease and 1 following second transplant. There was no mortality before 100 days post-transplant. At present, 0% in the first cohort, 25% in the second cohort, and 50% in the third cohort remain free of their disease. There was no Grade 2-4 acute or moderate to severe chronic graft-versus-host disease (GVHD). Therefore, we have shown that PT-Cy improves engraftment in patients with SCD who are at high risk for early mortality. As we reached stopping rules for the study, we opened a new protocol which adds additional immunosuppression in an attempt to improve the success rate while maintaining a low risk of GVHD. Since June 2017, 12 patients have been transplanted, 6 in the past year. All patients achieved high donor chimerism levels. One patient with history of stroke and chronic thromboembolic pulmonary hypertension on anticoagulation died 60 days after her second transplant. One of the 12 developed Grade 2 acute GVHD which responded well to steroids. We are planning to transplant 5 more patients by the end of this calendar year and 10 patients per year thereafter. We will also search for early biomarkers associated with graft rejection in an attempt to identify graft rejection at an early and potentially more reversible state and explore mechanisms of engraftment and tolerance induction. We also seek to identify whether patients are indeed tolerant of their grafts so that unnecessary immunosuppression can be discontinued.